title: NR4A2 is regulated by gastrin and influences cellular responses of gastric adenocarcinoma cells.
abstract: The peptide hormone gastrin is known to play a role in differentiation, growth and apoptosis of cells in the gastric mucosa. In this study we demonstrate that gastrin induces Nuclear Receptor 4A2 (NR4A2) expression in the adenocarcinoma cell lines AR42J and AGS-GR, which both possess the gastrin/CCK2 receptor. In vivo, NR4A2 is strongly expressed in the gastrin responsive neuroendocrine ECL cells in normal mucosa, whereas gastric adenocarcinoma tissue reveals a more diffuse and variable expression in tumor cells. We show that NR4A2 is a primary early transient gastrin induced gene in adenocarcinoma cell lines, and that NR4A2 expression is negatively regulated by inducible cAMP early repressor (ICER) and zinc finger protein 36, C3H1 type-like 1 (Zfp36l1), suggesting that these gastrin regulated proteins exert a negative feedback control of NR4A2 activated responses. FRAP analyses indicate that gastrin also modifies the nucleus-cytosol shuttling of NR4A2, with more NR4A2 localized to cytoplasm upon gastrin treatment. Knock-down experiments with siRNA targeting NR4A2 increase migration of gastrin treated adenocarcinoma AGS-GR cells, while ectopically expressed NR4A2 increases apoptosis and hampers gastrin induced invasion, indicating a tumor suppressor function of NR4A2. Collectively, our results uncover a role of NR4A2 in gastric adenocarcinoma cells, and suggest that both the level and the localization of NR4A2 protein are of importance regarding the cellular responses of these cells.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.forename: Linn-Karina Myrland
authors.initials: LK
authors.lastname: Selvik
authors.forename: Shalini
authors.initials: S
authors.lastname: Rao
authors.forename: Kristin
authors.initials: K
authors.lastname: Nørsett
authors.forename: Ingunn
authors.initials: I
authors.lastname: Bakke
authors.forename: Arne K
authors.initials: AK
authors.lastname: Sandvik
authors.forename: Astrid
authors.initials: A
authors.lastname: Lægreid
authors.forename: Torunn
authors.initials: T
authors.lastname: Bruland
authors.forename: Wenche S
authors.initials: WS
authors.lastname: Prestvik
authors.forename: Liv
authors.initials: L
authors.lastname: Thommesen
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000230:Adenocarcinoma / Q000378:metabolism*; D015153:Blotting, Western; D051817:Butyrate Response Factor 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D025461:Feedback, Physiological / Q000502:physiology; D005434:Flow Cytometry; D036681:Fluorescence Recovery After Photobleaching; D005755:Gastrins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D051817:Butyrate Response Factor 1; D005755:Gastrins; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D034741:RNA, Small Interfering; C102034:ZFP36L1 protein, human